Novel natural inhibitors targeting B-RAF(V600E) by computational study
| Autor: | Bo Wu, Gaojing Dou, Zhiyun Zhang, Hongyu Wang, Haoqun Xie, Dong Zhu, Junliang Ge, Xiaye Lv |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Drug CYP2D6 discovery studio media_common.quotation_subject Bioengineering Computational biology Molecular Dynamics Simulation Applied Microbiology and Biotechnology Mice Drug Discovery medicine Animals Humans B-raf(v600e) Distribution (pharmacology) Vemurafenib Protein Kinase Inhibitors ADME media_common Virtual screening Chemistry drug treatment General Medicine virtual screening Rats TP248.13-248.65 Databases Chemical V600E Research Article Research Paper Biotechnology medicine.drug Discovery Studio |
| Zdroj: | Bioengineered article-version (VoR) Version of Record Bioengineered, Vol 12, Iss 1, Pp 2970-2983 (2021) |
| ISSN: | 2165-5987 2165-5979 |
| DOI: | 10.1080/21655979.2021.1943113 |
| Popis: | The aim of this research was to screen the ZINC15 database to select lead compounds and drug candidates which can inhibit B-RAF (V600E). In order to identify drugs potentially inhibited B-RAF (V600E), numerous modules of Discovery Studio 4.5 were employed. Structure-based screening using LibDock was carried out followed by ADME (absorption, distribution, metabolism, excretion) and toxicity prediction. CDOCKER was performed to demonstrate the binding affinity and mechanism between ligands and B-RAF(V600E). To evaluate whether ligand-receptor complexes were stable, molecular dynamics were employed. Two novel natural compounds (ZINC000100168592 and ZINC000049784088) from ZINC15 database were found binding to B-RAF(V600E) with more favorable interaction energy in comparison with the reference drug Vemurafenib. Also, they were predicted with less ames mutagenicity, rodent carcinogenicity, non-developmental toxic potential and tolerance to cytochrome P450 2D6 (CYP2D6). The molecular dynamics simulation analysis indicated that the compound-B-RAF(V600E) complexes had more favorable potential energy compared with Vemurafenib and they can exist in natural environments stably. The result of this study shows that ZINC000100168592 and ZINC000049784088 are ideal leading potential compounds to inhibit B-RAF(V600E). The findings of this study and these selected drug candidates greatly contributed to the medication design and improvement of B-RAF(V600E) and other proteins. Graphical abstract |
| Databáze: | OpenAIRE |
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